Unlike most other organs, the brain and other CNS tissues cannot repair itself after injury. The failure of axons to regenerate in these situations is a major cause of sustained neurological deficits after events such as trauma and stroke. This proposal is designed to answer basic questions about why this regeneration fails to occur in order to informatively design therapeutic methods to promote regeneration in vivo. The model system used in this proposal is the retinal ganglion cell (RGC) neuron. RGCs are an excellent tool because they are the only CNS neurons that do not regenerate and can be cultured under conditions in which they will survive but do not regrow axons, allowing axonal regeneration to be specifically addressed. Postnatal (P8) cells re-extend axons in purified cultures at a rate approximately ten times slower than embryonic (E19) cells. This proposal examines why there is a difference in regenerative ability between embryonic and postnatal RGCs, and whether it is a result of intrinsic or extrinsic changes that have occurred in vivo between E19 and P8. In addition to being applicable to other CNS neurons, the use of RGCs allows regeneration in the visual system itself to be specifically elucidated. Glaucoma, optic neuritis, optic nerve ischemia and optic neuropathies all may result in the severing of RGC axons that results in blindness when they fail to regenerate.